Although primary prevention by tobacco use cessation and by moderation in alcohol intake should be the most successful strategy for control of head and neck cancer, the evaluation of complementary approaches, such as chemoprevention, is very important as a means toward achieving this goal. Natural and synthetic analogs of vitamin A (retinoids), beta-carotene, vitamin E and selenium are featured in the reported studies of chemoprevention of head and neck cancer. Literature data appear to support the notion that the chemopreventive efficacy of a mixture of vitamins and minerals is superior to a single agent. Data showing a reduction in the incidence and mortality rates of oral and other head and neck cancers as a result of large-scale intervention trials with chemopreventive agents are lacking. At this time, it appears premature to suggest supplementation of specific chemopreventive agents as a routine strategy to prevent head and neck cancer. Therefore, the basis of the present investigation is to systematically determine the efficacy of relevant agents, individually and in combination; initially, in well-defined animal model assays and with delineation of the mechanisms of action involved in etiology and prevention. We demonstrated the utility of the lacZ transgenic mouse for investigations involving initiation pf carcinogenesis of the oral cavity by synthetic 4-nitroquinoline-N-oxide (4-NQO), as well as carcinogens present in tobacco and its pyrolysis products (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] and benzo(a)pyrene [BaP]). We also demonstrated that a diet supplemented with a synthetic organoselenium compound (1,4-phenylenebis(methylene)selenocyanate, p-XSC)) or with vitamin E and C in several organs, including oral tissues, can inhibit mutagenesis to varying extents and the system can be used to evaluate other chemopreventive agents. In addition, we have shown that, in F344 rats, p-XSC can inhibit tumors of the tongue and block the cell proliferation induced by 4-NQO. Furthermore, results obtained in our laboratory, as well as in others, clearly demonstrate that a form of selenium compound, not selenium per se, is critical in cancer chemoprevention. On the basis of our preliminary results and those reported in the literature, we hypothesize that the combination of selenium in the form of p-XSC or the naturally-occurring Se-methylselenocysteine (MSC), vitamin A, and E should prove to be highly promising cocktail for chemoprevention of cancer of the oral cavity. Specifically, this cocktail will inhibit oxidative damage, cell proliferation and COX-2 activity; this will result in induction of apoptosis and inhibition of tumorigenesis. To test our hypothesis, our specific aims are: 1. To determine the inhibition of mutagenesis induced by 4-NQO and BaP in the oral cavity of the lacZ transgenic mouse by selenium (MSC and p-XSC), vitamin A, and E individually and in combination. 2. To determine the chemopreventive efficacy of the most effective cocktail (developed in Aim 1) against the development of tumors of the tongue induced by 4-NQO and BaP in male F344 rats, and in female B6C3F mice, respectively. 3. To examine the effect of the cocktail on critical intermediate biomarkers (cell proliferation, oxidative, DNA damage, COX-activities, and apoptosis) in the tongue of the rat and mouse. The results of this project will provide insights regarding the feasibility of using the most effective cocktail in future clinical trials toward chemoprevention of oral cancer.